T. SuithichaiyakulCardiomed Chula

The cardiovascular (CV) continuum:role of risk factors

Dzau VJ, et al. Circulation 2006;114:2850–2870; Figure adapted from Dzau V, Braunwald E. Am Heart J 1991;121:1244–1263; Yusuf S, et al. Lancet 2004;364:937–952

Intervention at any point along the chain of events may modify cardiovascular disease progression and provide cardioprotection

*An additive effect of risk factors has been shown in the risk for a CV event

Cardio/ cerebrovascular

death

End-stagerenal

disease

Nephroticproteinuria

Macro-proteinuria

Micro-albuminuria

Endothelialdysfunction

Risk factors*: hypertension, diabetes, obesity, smoking, age

Atherosclerosis and left ventricular hypertrophy

Myocardialinfarction &

stroke

RemodellingVentricular dilation/

cognitive dysfunction

Congestive heart failure/secondary stroke

End-stageheart disease,brain damageand dementia

EndothelialDysfunction

Target OrganDamage

Vasan et al. N Engl J Med. 2001;345:1291-1297.

Men Women

1086

420

Time (years)

0 2 4 6 8 10 12 14

P<.001

Cum

ulat

ive

Inci

denc

e (%

) 14121086420

0

Time (years)

2 4 6 8 10 12 14

P<.001

High normal 130-139/85-89 mm HgNormal 120-129/80-84 mm HgOptimal <120/80 mm Hg

Prehypertension

HighHigh--Normal Blood Pressure and CVD Risk: Normal Blood Pressure and CVD Risk: Framingham StudyFramingham Study

BP as a CV RiskBP as a CV RiskC

V m

orta

lity

risk

CV

mor

talit

y ris

k

SBP/DBP (mmHg)SBP/DBP (mmHg)

001122334455667788

115/75115/75 135/85135/85 155/95155/95 175/105175/105

2x2x

4x4x

8x8x

Lewington et al. Lancet 2002;360:1903–13

CV mortality risk doubles with each 20/10 mmHg increment CV mortality risk doubles with each 20/10 mmHg increment

Age 40Age 40––69 years69 years

Goals Goals ofof TherapyTherapy

Reduce CVD and renal morbidity and mortality.

Treat to BP <140/90 mmHg or BP <130/80 mmHg in patients with diabetes or chronic kidney disease.

Achieve SBP goal especially in persons >50 years of age.

JNC-VII, 2003

Relationship Between SBP Reductionand CV Mortality

Relationship Between SBP Reductionand CV Mortality

CV, cardiovascular; SBP, systolic blood pressure.Staessen JA et al. Lancet. 2001;358:1305-1315.

1.50

1.25

1.00

0.75

0.50

0.25

0 5 10 15 20 25

Odds ratio for CV

mortality (experimental

/ reference)

HOPE

MIDAS/NICS/VHAS

UKPDS C vs A

NORDIL INSIGHTHOT L vs H

HOT M vs HSTOP ACEIs

STOP CCBs

CAPPP UKPDS L vs HSyst-China

STONESyst-Eur

MRC1MRC2

SHEP HEPEWPHE

RCT70-80

STOP-1PART 2/SCAT

ATMH

-5Difference in SBP (mm Hg)

8

Blood Pressure ReductionBlood Pressure ReductionBlood Pressure Reduction• Meta-analysis of 61 prospective, observational studies

• One million adults

• 12.7 million person-years

• Meta-analysis of 61 prospective, observational studies

• One million adults

• 12.7 million person-years

2 mmHg decrease in mean systolic blood pressure 10% reduction

in risk of stroke mortality

7% reduction in risk of ischemic heart disease mortality

1. Lewington S et al. Lancet. 2002;360:1903–1913.

Hypertension guidelinesTarget BP

Hypertension guidelinesTarget BP

Guidelines Target BPBHS IV 20041 ≤140/85mmHg

≤130/80mmHg in patients with diabetes

ESC/ESH 20032

ESC/ESH 2007

≤140/90mmHg≤130/80mmHg in patients with diabetes≤130/80mmHg in DM, stroke, MI, Renal dysfunction, Proteinuria

JNC VII 20033 ≤140/90mmHg ≤130/80mmHg in patients with diabetes or renal disease

WHO/ISH 19994 ≤140/90mmHg ≤130/85mmHg in patients with diabetes

1. Williams B, et al. J Human Hypertens 2004;18:139–85.2. ESC/ESH. J Hypertens 2003;21:1011–53. 3. Chobanian AV, et al. JAMA 2003;289:2560–72.4. WHO/ISH. J Hypertens 1999;17:151–83.

Thai Hypertension GuidelineThai Hypertension Guideline

Cushman WC, et al. NEJM 2010;362:1575-1585

BP AchievementBP Achievement139.2/76 mmHg 133.5/70.5 mmHg

119.3/64.4 mmHg

Cushman WC, et al. NEJM 2010;362:1575-1585

ResultsResultsCushman WC, et al. NEJM 2010;362:1575-1585

HOT

Slim Jim /NK/1 14/05/20041

HypertensionOptimalTreatmentInternational Study

HypertensionOptimalTreatmentInternational Study

Study resultsStudy results

HOT studyHOT study

142.2 mmHg

142.2 mmHg

138.5 mmHg

130.0 mmHg

86.5 mmHg

82.5 mmHg

VALUEVALUE

Valsartan Antihypertensive Long-Term Use Evaluation

Julius S et al. Lancet. June 2004;363:2022–31.

Risk of Primary Event and DBP

02468

101214161820

<70 70-80 80-90 >90 mmHg(n=971) (n=5575) (n=7337) (n=1381)

Haz

ard

of p

rimar

y en

dpoi

nt %

13.3 9.4 18.79.4

HR 1.48(1.233-1.773)

P<0.0001

HR 2.37(2.668-2.711)

P<0.0001

Nadir = 79 mmHg

Risk of Stroke and DBP

0123456789

10

<70 70-80 80-90 >90 mmHg(n=971) (n=5575) (n=7337) (n=1381)

Haz

ard

of S

toke

%

HR 0.84(0.61-1.185)

P=0.3267

HR 3.47(2.822-4.258)

P<0.0001

Nadir < 60 mmHg

Non Fatal MI and Fatal CADNon Fatal MI and Fatal CAD

ONgoing Telmisartan Alone and in combination

with Ramipril Global Endpoint Trial

ONgoing Telmisartan Alone and in combination

with Ramipril Global Endpoint Trial

The HYpertensionin the

Very Elderly Trial

N. Beckett, R. Peters, A. Fletcher, C. Bulpitton behalf of the HYVET committees and

investigators

HYVET

• Results• Mean BP at the end of the trial

• Indapamide +/- perindopril - 143/78 mm Hg• Placebo – 158/84 mm Hg

• 48.0% of indapamide patients achieved goal BP vs. 19.9% of placebo patients (p<0.001)

• Outcomes with indapamide +/- perindopril• 30% reduction in stroke (p=0.06)• 64% reduction in heart failure (p<0.001)• 21% reduction in all-cause mortality (p=0.02)

Beckett NS et al. N Engl J Med 2008;358:1887‐98.

Per-Protocol

HR 95% CI

- 34% 0.46 - 0.95

0.59 - 0.88

0.33 - 0.93

0.55-0.97

0.17-0.48

0.51-0.71

- 28%

- 45%

Cardiovascular mortality -27% 0.029

-72%

- 37%

P

0.025

0.001

0.021

<0.001

<0.001

All stroke

Total mortality

Fatal stroke

Heart failure

Cardiovascular events

Target BPTarget BP

Report from the panel members appointed to the Eighth Joint National Committee (JNC 8)

JAMA. doi:10.1001/jama.2013.284427. Published online December 18, 2013.

Recommendation 1(Strong recommendation)

Recommendation 2(Strong recommendation)

Recommendation 3(Expert opinion)

Recommendation 1(Strong recommendation)

Recommendation 2(Strong recommendation)

Recommendation 3(Expert opinion)

General population ≥60 

years

SBP ≥150 mm Hgor DBP ≥90 mm Hg 

SBP <150 mm Hgand DBP <90 mm Hg 

General population <60 

years

DBP ≥90 mm Hg  DBP <90 mm Hg 

General population <60 years

SBP ≥140 mm Hg  SBP <140 mm Hg 

Goals

Recommendations (1/3)Recommendations (1/3)

JAMA. doi:10.1001/jama.2013.284427. Published online December 18, 2013.

BP thresholds 

SBP ≥150 mm Hgor DBP ≥90 mm Hg 

SBP <150 mm Hgand DBP <90 mm Hg 

2015 Thai Guideline

Target BPTarget BP

SPRINT Research QuestionSPRINT Research Question

Examine effect of more intensive high blood pressure treatment than is currently recommended

Randomized Controlled TrialTarget Systolic BP

Intensive Treatment  Goal SBP < 120 mm Hg

Standard TreatmentGoal SBP < 140 mm Hg 

SPRINT ‐ The Systolic Blood Pressure Intervention Trial N Engl J Med 2015;373:2103‐16.

Demographic and Baseline CharacteristicsDemographic and Baseline Characteristics

TotalN=9361

IntensiveN=4678

StandardN=4683

Mean (SD) age, years 67.9 (9.4) 67.9 (9.4) 67.9 (9.5)% ≥75 years 28.2% 28.2% 28.2%

Female, % 35.6% 36.0% 35.2%White, % 57.7% 57.7% 57.7%African-American, % 29.9% 29.5% 30.4%Hispanic, % 10.5% 10.8% 10.3%Prior CVD, % 20.1% 20.1% 20.0%Mean 10-year Framingham CVD risk, % 20.1% 20.1% 20.1%

Taking antihypertensive meds, % 90.6% 90.8% 90.4%Mean (SD) number of antihypertensive

meds1.8 (1.0) 1.8 (1.0) 1.8 (1.0)

Mean (SD) Baseline BP, mm HgSystolic 139.7

(15.6)139.7 (15.8)

139.7 (15.4)Diastolic 78.1 (11.9) 78.2 (11.9) 78.0 (12.0)

Selected Baseline Laboratory CharacteristicsSelected Baseline Laboratory Characteristics

TotalN=9361

IntensiveN=4678

StandardN=4683

Mean (SD) eGFR, mL/min/1.73 m2 71.7 (20.6) 71.8 (20.7) 71.7 (20.5)

% with eGFR<60 mL/min/1.73m2 28.3 28.4 28.1

Mean (SD) Urine albumin/creatinine, mg/g

42.6 (166.3) 44.1 (178.7) 41.1 (152.9)

Mean (SD) Total cholesterol, mg/dL 190.1 (41.2) 190.2 (41.4) 190.0 (40.9)

Mean (SD) Fasting plasma glucose, mg/dL

98.8 (13.5) 98.8 (13.7) 98.8 (13.4)

Primary Outcome and Primary HypothesisPrimary Outcome and Primary Hypothesis

• Primary outcome• CVD composite: first occurrence of

• MI• ACS (non-MI ACS)• Stroke• Acute decompensated HF• CVD

• Primary hypothesis*• CVD composite event rate lower

in intensive compared to standard treatment

• Primary outcome• CVD composite: first occurrence of

• MI• ACS (non-MI ACS)• Stroke• Acute decompensated HF• CVD

• Primary hypothesis*• CVD composite event rate lower

in intensive compared to standard treatment

* Expected 4‐6 yrs of follow‐up (actual 3.76 yrs.) 

Systolic BP During Follow‐up

Mean SBP136.2 mm Hg

Mean SBP121.4 mm Hg

Average SBP(During Follow‐up)

Standard: 134.6 mm Hg

Intensive: 121.5 mm Hg

Average number ofantihypertensivemedications

Number ofparticipants

Standard

Intensive

Year 1

Number ofParticipants

Hazard Ratio = 0.75 (95% CI: 0.64 to 0.89)

Standard

Intensive(243 events)

During Trial (median follow‐up = 3.26 yrs)Number Needed to Treat (NNT)to prevent a primary outcome = 61

SPRINT Primary Outcome Cumulative HazardSPRINT Primary Outcome Cumulative Hazard

(319 events)

SPRINT Primary Outcome and its Components Event Rates and Hazard Ratios 

SPRINT Primary Outcome and its Components Event Rates and Hazard Ratios 

Intensive Standard

No. of Events

Rate, %/year

No. of Events

Rate, %/year

HR (95% CI) P value

Primary Outcome 243 1.65 319 2.19 0.75 (0.64, 0.89)

<0.001

All MI 97 0.65 116 0.78 0.83 (0.64, 1.09)

0.19

Non-MI ACS 40 0.27 40 0.27 1.00 (0.64, 1.55)

0.99

All Stroke 62 0.41 70 0.47 0.89 (0.63, 1.25)

0.50

All HF 62 0.41 100 0.67 0.62 (0.45, 0.84)

0.002

CVD Death 37 0.25 65 0.43 0.57 (0.38, 0.85)

0.005

Primary Outcome Experience in the Six Pre‐specified Subgroups of Interest

Primary Outcome Experience in the Six Pre‐specified Subgroups of Interest

*Treatment by subgroup interaction 

Adapt from Figure 2B in the N Engl J Med manuscript

Include NNT

All‐cause Mortality Cumulative Hazard All‐cause Mortality Cumulative Hazard 

Hazard Ratio = 0.73 (95% CI: 0.60 to 0.90)

During Trial (median follow‐up = 3.26 yrs)Number Needed to Treat (NNT)

to Prevent a death = 90

Standard(210 deaths)

Intensive(155 deaths)

Number ofParticipants

All‐cause Mortality Experience in the Six Pre‐specified Subgroups of Interest

All‐cause Mortality Experience in the Six Pre‐specified Subgroups of Interest

*

*p=0.34, after Hommel adjustment for multiple comparisons